Piezo2 Mediates Low-Threshold Mechanically Evoked Pain in the Cornea

Fernández-Trillo, Jorge; Florez-Paz, Danny M.; Íñigo-Portugués, Almudena; González-González, Omar; Campo, Ana Gómez del; González, Alejandro; Viana, Félix; Belmonte, Carlos; Gomis, Ana

doi:10.1523/jneurosci.0247-20.2020

Cited by 53 publications

(54 citation statements)

References 60 publications

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“…It was demonstrated that, compared to TRPV1 neurons, TRPM8-IR corneal nerve endings in both guinea pig and mouse corneal epithelia had complex (longer and more branched) morphology (Ivanusic et al, 2013;Alamri et al, 2015Alamri et al, , 2018He et al, 2019) (Figure 1). The presence of Piezo2 + channels has been recently found in corneal nerve fibers in mice (Fernandez-Trillo et al, 2020).…”

Section: Functional Classification Of Corneal Fibersmentioning

confidence: 90%

Morphological and Functional Changes of Corneal Nerves and Their Contribution to Peripheral and Central Sensory Abnormalities

Guerrero-Moreno

Baudouin

Mélik-Parsadaniantz

et al. 2020

Front. Cell. Neurosci.

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The cornea is the most densely innervated and sensitive tissue in the body. The cornea is exclusively innervated by C- and A-delta fibers, including mechano-nociceptors that are triggered by noxious mechanical stimulation, polymodal nociceptors that are excited by mechanical, chemical, and thermal stimuli, and cold thermoreceptors that are activated by cooling. Noxious stimulations activate corneal nociceptors whose cell bodies are located in the trigeminal ganglion (TG) and project central axons to the trigeminal brainstem sensory complex. Ocular pain, in particular, that driven by corneal nerves, is considered to be a core symptom of inflammatory and traumatic disorders of the ocular surface. Ocular surface injury affecting corneal nerves and leading to inflammatory responses can occur under multiple pathological conditions, such as chemical burn, persistent dry eye, and corneal neuropathic pain as well as after some ophthalmological surgical interventions such as photorefractive surgery. This review depicts the morphological and functional changes of corneal nerve terminals following corneal damage and dry eye disease (DED), both ocular surface conditions leading to sensory abnormalities. In addition, the recent fundamental and clinical findings of the importance of peripheral and central neuroimmune interactions in the development of corneal hypersensitivity are discussed. Next, the cellular and molecular changes of corneal neurons in the TG and central structures that are driven by corneal nerve abnormalities are presented. A better understanding of the corneal nerve abnormalities as well as neuroimmune interactions may contribute to the identification of a novel therapeutic targets for alleviating corneal pain.

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Section: Functional Classification Of Corneal Fibersmentioning

confidence: 90%

Morphological and Functional Changes of Corneal Nerves and Their Contribution to Peripheral and Central Sensory Abnormalities

Guerrero-Moreno

Baudouin

Mélik-Parsadaniantz

et al. 2020

Front. Cell. Neurosci.

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“…In addition, topical capsazepine administration decreased corneal mechanical allodynia in DED animals, suggesting key involvement of polymodal nociceptors in the mechanical allodynia associated with DED. In a recent study, Fernández-Trillo et al demonstrated that Piezo2 channels are present in the cell body and nerve endings of corneal neurons [ 68 ]. They used several modalities and multimodal approaches to show that Piezo2 channels contribute to mechanical sensitivity in sensory nerve endings of pure corneal mechanoreceptors and polymodal nociceptors.…”

Section: Discussionmentioning

confidence: 99%

Capsazepine decreases corneal pain syndrome in severe dry eye disease

Fakih

Guerrero-Moreno

Baudouin

et al. 2021

J Neuroinflammation

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Background Dry eye disease (DED) is a multifactorial disease of the ocular surface accompanied by neurosensory abnormalities. Here, we evaluated the effectiveness of transient receptor potential vanilloid-1 (TRPV1) blockade to alleviate ocular pain, neuroinflammation, and anxiety-like behavior associated with severe DED. Methods Chronic DED was induced by unilateral excision of the Harderian and extraorbital lacrimal glands of adult male mice. Investigations were conducted at 21 days after surgery. The mRNA levels of TRPV1, transient receptor potential ankyrin-1 (TRPA1), and acid-sensing ion channels 1 and 3 (ASIC1 and ASIC3) in the trigeminal ganglion (TG) were evaluated by RNAscope in situ hybridization. Multi-unit extracellular recording of ciliary nerve fiber activity was used to monitor spontaneous and stimulated (cold, heat, and acid) corneal nerve responsiveness in ex vivo eye preparations. DED mice received topical instillations of the TRPV1 antagonist (capsazepine) twice a day for 2 weeks from d7 to d21 after surgery. The expression of genes involved in neuropathic and inflammatory pain was evaluated in the TG using a global genomic approach. Chemical and mechanical corneal nociception and spontaneous ocular pain were monitored. Finally, anxiety-like behaviors were assessed by elevated plus maze and black and white box tests. Results First, in situ hybridization showed DED to trigger upregulation of TRPV1, TRPA1, ASIC1, and ASIC3 mRNA in the ophthalmic branch of the TG. DED also induced overexpression of genes involved in neuropathic and inflammatory pain in the TG. Repeated instillations of capsazepine reduced corneal polymodal responsiveness to heat, cold, and acidic stimulation in ex vivo eye preparations. Consistent with these findings, chronic capsazepine instillation inhibited the upregulation of genes involved in neuropathic and inflammatory pain in the TG of DED animals and reduced the sensation of ocular pain, as well as anxiety-like behaviors associated with severe DED. Conclusion These data provide novel insights on the effectiveness of TRPV1 antagonist instillation in alleviating abnormal corneal neurosensory symptoms induced by severe DED, opening an avenue for the repositioning of this molecule as a potential analgesic treatment for patients suffering from chronic DED.

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“…As a Ca 2+ -permeable nonselective cation channel, Piezo has been found to participate in several processes. Recently, the Piezo2 has been already found to express in A-type nerve fibers of trigeminal ganglion for pselaphesia afference [ 7 , 9 , 17 ]. Then, is there any possibility of Piezo2 expression in those allodynia afferent neurons?…”

Section: Discussionmentioning

confidence: 99%

“…It was observed that, in Piezo2-deficient mice, dynamic allodynia following nerve injury was absent [ 6 ]. This implied the mechanoreceptor could act as an essential mediator of tactile allodynia under inflammatory conditions [ 7 – 9 ]. Previous studies have observed administration of IL-6 neutralizing antibody may significantly decrease the allodynia.…”

Section: Introductionmentioning

confidence: 99%